Nedd4 (neural precursor cell expressed developmentally down-regulated 4, Nedd4-1) encodes a HECT-type E3 ubiquitin-protein ligase composed of an N-terminal Ca2+/lipid-binding C2 domain, three WW domains and a C-terminal HECT catalytic domain. The WW domains recognize proline-rich PY motifs (L/PPxY) in substrates, first shown for the epithelial Na+ channel (ENaC) subunits, and the HECT domain accepts ubiquitin from an E2 as a thioester on its catalytic cysteine and transfers it to substrate lysines, favouring monoubiquitination and K63-linked chains. Nedd4 is predominantly cytoplasmic and is recruited to the plasma membrane and endosomes, where ubiquitination of membrane proteins such as ENaC, receptor tyrosine kinases (IGF1R, FGFR1) and the AMPA receptor subunit GluA1 drives their endocytosis and lysosomal degradation. In neurons Nedd4 mono-ubiquitinates the small GTPase Rap2A in a complex with TNIK, promoting dendrite growth and arborization, and it controls activity-dependent internalization and lysosomal sorting of AMPA receptors. Nedd4 is broadly expressed (highest in lung, kidney and brain) and developmentally down-regulated in brain; mouse knockouts reveal requirements in heart and vascular development, neuromuscular junction formation and T-cell activation. Its protein level rises in denervated, atrophying skeletal muscle.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Nedd4 is not a transcriptional regulator; effects on transcription (e.g. Tsp-1 levels in knockout cells, RNAPII ubiquitination after UV) are indirect. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Indirect effect of the ligase; over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Nedd4 is not a transcriptional regulator; effects on transcription (e.g. Tsp-1 levels in knockout cells, RNAPII ubiquitination after UV) are indirect. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Indirect effect of the ligase; over-annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells |
| GO:0000151 ubiquitin ligase complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 is a single-subunit HECT E3 that forms complexes with adaptors/activators (NDFIP1/2) and with USP13. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Acceptable as a description of its adaptor-containing complexes, but the catalytic activity does not require a multi-subunit complex. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase |
| GO:0000785 chromatin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Chromatin association transferred from human NEDD4, plausibly linked to its recruitment to stalled RNA polymerase II after UV damage. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral, context-specific localization. Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells |
| GO:0002250 adaptive immune response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-deficient mouse T cells proliferate less and give inadequate B cell help; Nedd4 promotes Cbl-b degradation. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Supported organismal role via a specific substrate; non-core. Supporting Evidence: PMID:18931680 Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation PMID:18931680 Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells |
| GO:0003151 outflow tract morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-1 knockout mice show double-outlet right ventricle. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Developmental phenotype in mouse knockout, upstream/indirect; non-core. Supporting Evidence: PMID:20026598 disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities |
| GO:0003197 endocardial cushion development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-1 knockout mice show atrioventricular cushion defects. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Developmental phenotype; non-core. Supporting Evidence: PMID:20026598 disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:20159449 Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls... | MODIFY | Summary: Correct but more general parent of the E3 ligase activity Nedd4 performs as a HECT E3. Reason: Ubiquitin-protein transferase activity is true but GO:0061630 ubiquitin protein ligase activity (an is_a descendant already carried by this gene) is the precise term for a HECT E3 that transfers ubiquitin from E2 thioester to substrate lysines. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000120 | MODIFY | Summary: Correct but more general parent of the E3 ligase activity Nedd4 performs as a HECT E3. Electronic (IEA) mapping. Reason: Ubiquitin-protein transferase activity is true but GO:0061630 ubiquitin protein ligase activity (an is_a descendant already carried by this gene) is the precise term for a HECT E3 that transfers ubiquitin from E2 thioester to substrate lysines. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A minor nuclear pool exists; Nedd4 carries a nuclear export signal and is predominantly cytoplasmic. Electronic (IEA) mapping. Reason: Correct but peripheral localization. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus file:rat/Nedd4/Nedd4-uniprot.txt Nuclear export signal |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: A minor nuclear pool exists; Nedd4 carries a nuclear export signal and is predominantly cytoplasmic. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Correct but peripheral localization. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus file:rat/Nedd4/Nedd4-uniprot.txt Nuclear export signal |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A minor nuclear pool exists; Nedd4 carries a nuclear export signal and is predominantly cytoplasmic. Orthology transfer (ISS) from UniProtKB:P46934. Reason: Correct but peripheral localization. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus file:rat/Nedd4/Nedd4-uniprot.txt Nuclear export signal |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Minor nucleoplasmic pool transferred from human NEDD4. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral localization consistent with the minor nuclear pool. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus |
| GO:0005737 cytoplasm | EXP PMID:20159449 Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls... | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. Electronic (IEA) mapping. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Nedd4 is predominantly cytoplasmic; shown for rat Nedd4 in neurons and supported by orthologs and phylogeny. Orthology transfer (ISS) from UniProtKB:P46934. Reason: Main site of the ligase; consistent experimental and inferred evidence. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0005794 Golgi apparatus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Golgi localization transferred from human; brain fractionation shows modest enrichment of Nedd4-1 in ER/Golgi membranes. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Organelle claim holds at the root level (fractionation and ortholog data) but is peripheral to the function. Supporting Evidence: PMID:20159449 In the adult mouse brain, Nedd4-1 is slightly enriched in ER- and Golgi membranes |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Soluble cytosolic pool of Nedd4, consistent with its predominantly cytoplasmic distribution. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Cytosol is the appropriate specific compartment for a soluble peripheral-membrane E3. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Soluble cytosolic pool of Nedd4, consistent with its predominantly cytoplasmic distribution. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Cytosol is the appropriate specific compartment for a soluble peripheral-membrane E3. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Predominantly cytoplasmic but also located in the nucleus |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nedd4 is a peripheral membrane protein recruited to the plasma membrane (C2 domain, GRB10) where it ubiquitinates membrane substrates such as ENaC and receptor tyrosine kinases. Electronic (IEA) mapping. Reason: Site where the ligase acts on its main membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is a peripheral membrane protein recruited to the plasma membrane (C2 domain, GRB10) where it ubiquitinates membrane substrates such as ENaC and receptor tyrosine kinases. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Site where the ligase acts on its main membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is a peripheral membrane protein recruited to the plasma membrane (C2 domain, GRB10) where it ubiquitinates membrane substrates such as ENaC and receptor tyrosine kinases. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Site where the ligase acts on its main membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Nedd4 is a peripheral membrane protein recruited to the plasma membrane (C2 domain, GRB10) where it ubiquitinates membrane substrates such as ENaC and receptor tyrosine kinases. Orthology transfer (ISS) from UniProtKB:P46934. Reason: Site where the ligase acts on its main membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes |
| GO:0005902 microvillus | IDA PMID:9227416 Immunolocalization of the ubiquitin-protein ligase Nedd4 in ... | KEEP AS NON CORE | Summary: Immunostaining of rat kidney detected Nedd4 at microvillar borders of proximal convoluted tubules. Reason: Direct rat observation (abstract-level); tissue-specific peripheral localization. Supporting Evidence: PMID:9227416 microvillar borders of proximal convoluted tubules expressed variable amounts of rNedd4 |
| GO:0005938 cell cortex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cortical localization transferred from human, consistent with peripheral recruitment to the plasma membrane. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral localization. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 |
| GO:0006511 ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Nedd4-mediated ubiquitination targets substrates (ENaC, GluA1, receptor tyrosine kinases, DAZAP2) for proteasomal or lysosomal degradation. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Core outcome of the ligase activity, supported by phylogenetic inference and orthologous experiments. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Nedd4-mediated ubiquitination targets substrates (ENaC, GluA1, receptor tyrosine kinases, DAZAP2) for proteasomal or lysosomal degradation. Electronic (IEA) mapping. Reason: Core outcome of the ligase activity, supported by phylogenetic inference and orthologous experiments. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4-mediated ubiquitination targets substrates (ENaC, GluA1, receptor tyrosine kinases, DAZAP2) for proteasomal or lysosomal degradation. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Core outcome of the ligase activity, supported by phylogenetic inference and orthologous experiments. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4-mediated ubiquitination targets substrates (ENaC, GluA1, receptor tyrosine kinases, DAZAP2) for proteasomal or lysosomal degradation. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Core outcome of the ligase activity, supported by phylogenetic inference and orthologous experiments. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0006511 ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Nedd4-mediated ubiquitination targets substrates (ENaC, GluA1, receptor tyrosine kinases, DAZAP2) for proteasomal or lysosomal degradation. Orthology transfer (ISS) from UniProtKB:P46934. Reason: Core outcome of the ligase activity, supported by phylogenetic inference and orthologous experiments. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0006513 protein monoubiquitination | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 monoubiquitinates Rap2A and IGF1R. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Well supported mode of substrate modification. Supporting Evidence: PMID:20159449 indicating monoubiquitination of Rap2A by EGFP-Nedd4-1 file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes |
| GO:0006622 protein targeting to lysosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 contributes to lysosomal sorting of LAPTM4B. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral, substrate-specific process. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B |
| GO:0006955 immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad immune term. The rat IEP row rests on Nedd4 partitioning into lipid rafts after IgE stimulation of RBL mast cells, which is relocalization rather than a demonstrated immune role; the ARBA row is a model prediction. Electronic (IEA) mapping. Reason: Retained only because the mouse T-cell work supports the more specific adaptive immune response; the rat evidence alone would not justify it. Supporting Evidence: PMID:11248052 both ligases become associated with lipid rafts after activation of IgE signaling PMID:18931680 Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells |
| GO:0006955 immune response | IEP PMID:11248052 Raft-partitioning of the ubiquitin ligases Cbl and Nedd4 upo... | KEEP AS NON CORE | Summary: Broad immune term. The rat IEP row rests on Nedd4 partitioning into lipid rafts after IgE stimulation of RBL mast cells, which is relocalization rather than a demonstrated immune role; the ARBA row is a model prediction. Reason: Retained only because the mouse T-cell work supports the more specific adaptive immune response; the rat evidence alone would not justify it. Supporting Evidence: PMID:11248052 both ligases become associated with lipid rafts after activation of IgE signaling PMID:18931680 Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells |
| GO:0006974 DNA damage response | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 ubiquitylates RNA polymerase II in response to UV-induced DNA damage. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Supported by ortholog data; peripheral to the main membrane-trafficking role. Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells |
| GO:0007041 lysosomal transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transport of ubiquitinated cargo to lysosomes. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Broadly true via endocytic sorting of substrates; peripheral description. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0007528 neuromuscular junction development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nedd4-null mice have abnormal neuromuscular junctions, through non-cell autonomous mechanisms. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Supported by mouse genetics and phylogenetic inference; non-core developmental role. Supporting Evidence: PMID:19345204 Nedd4 is involved in regulating the formation and function of the NMJs through non-cell autonomous mechanisms |
| GO:0007528 neuromuscular junction development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-null mice have abnormal neuromuscular junctions, through non-cell autonomous mechanisms. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Supported by mouse genetics and phylogenetic inference; non-core developmental role. Supporting Evidence: PMID:19345204 Nedd4 is involved in regulating the formation and function of the NMJs through non-cell autonomous mechanisms |
| GO:0010646 regulation of cell communication | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of cell communication is entailed by more specific signalling-regulation terms kept here (negative regulation of VEGFR signaling pathway; postsynaptic protein catabolism modulating synaptic transmission). Electronic (IEA) mapping. Reason: ARBA term without added information. |
| GO:0010766 negative regulation of sodium ion transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 suppresses ENaC-mediated sodium transport through ubiquitination of the channel. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Supported but physiologically secondary to Nedd4-2; non-core. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention PMID:9351815 Our results suggest that ENaC function is regulated by ubiquitination |
| GO:0010766 negative regulation of sodium ion transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 suppresses ENaC-mediated sodium transport through ubiquitination of the channel. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Supported but physiologically secondary to Nedd4-2; non-core. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention PMID:9351815 Our results suggest that ENaC function is regulated by ubiquitination |
| GO:0014894 response to denervation involved in regulation of muscle adaptation | IEP PMID:19125695 The inositol phosphatase MTMR4 is a novel target of the ubiq... | KEEP AS NON CORE | Summary: In rat gastrocnemius denervation-induced atrophy, Nedd4 protein increased about 2-fold while its candidate substrate MTMR4 fell. This is an expression response; the ubiquitination assays in the same paper used human NEDD4 and MTMR4. Reason: Valid IEP for a response term; describes regulation of Nedd4 levels during muscle atrophy rather than its molecular role. Supporting Evidence: PMID:19125695 Quantification of the blots with CCD acquisition of the chemiluminescence signal shows that MTMR4 decreases approx. 90% with a 2-fold increase in Nedd4 expression |
| GO:0016020 membrane | ISO GO_REF:0000121 | MODIFY | Summary: Membrane association is real but the generic term is less informative than the supported plasma membrane location. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Refine to GO:0005886 plasma membrane, already carried by this gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: plasma membrane Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Recruited to the plasma membrane by GRB10 |
| GO:0016248 channel inhibitor activity | ISO GO_REF:0000121 | TOO GENERAL | Summary: Channel inhibitor activity is entailed by sodium channel inhibitor activity, which is kept in this review. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Uninformative parent of GO:0019871 sodium channel inhibitor activity asserted elsewhere for this gene. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: Nedd4 ubiquitinates many substrates (Rap2A, ENaC, GluA1, IGF1R, FGFR1). Electronic (IEA) mapping. Reason: Direct consequence of the core E3 activity. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0016567 protein ubiquitination | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 ubiquitinates many substrates (Rap2A, ENaC, GluA1, IGF1R, FGFR1). Orthology transfer (ISO) from MGI:MGI:97297. Reason: Direct consequence of the core E3 activity. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0016567 protein ubiquitination | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 ubiquitinates many substrates (Rap2A, ENaC, GluA1, IGF1R, FGFR1). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Direct consequence of the core E3 activity. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0016567 protein ubiquitination | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 ubiquitinates many substrates (Rap2A, ENaC, GluA1, IGF1R, FGFR1). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Direct consequence of the core E3 activity. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0016567 protein ubiquitination | ISS GO_REF:0000024 | ACCEPT | Summary: Nedd4 ubiquitinates many substrates (Rap2A, ENaC, GluA1, IGF1R, FGFR1). Orthology transfer (ISS) from UniProtKB:P46934. Reason: Direct consequence of the core E3 activity. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used |
| GO:0019870 potassium channel inhibitor activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human NEDD4, which can down-regulate potassium channels via ubiquitination-dependent removal. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Plausible family-level effect mediated by the ligase activity rather than direct channel blockade; peripheral to the core function. |
| GO:0019871 sodium channel inhibitor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nedd4 binds ENaC PY motifs and reduces channel activity by ubiquitination-driven internalization and degradation rather than by direct gating block. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: The PAINT/ISO assertion is consistent with Nedd4-family suppression of ENaC, but the effect is a consequence of the E3 ligase activity (surface removal), and in vivo the paralog Nedd4-2 is the dominant ENaC regulator. Kept as non-core. Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) PMID:9351815 Our results suggest that ENaC function is regulated by ubiquitination file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention |
| GO:0019871 sodium channel inhibitor activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 binds ENaC PY motifs and reduces channel activity by ubiquitination-driven internalization and degradation rather than by direct gating block. Orthology transfer (ISO) from MGI:MGI:97297. Reason: The PAINT/ISO assertion is consistent with Nedd4-family suppression of ENaC, but the effect is a consequence of the E3 ligase activity (surface removal), and in vivo the paralog Nedd4-2 is the dominant ENaC regulator. Kept as non-core. Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) PMID:9351815 Our results suggest that ENaC function is regulated by ubiquitination file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention |
| GO:0019871 sodium channel inhibitor activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 binds ENaC PY motifs and reduces channel activity by ubiquitination-driven internalization and degradation rather than by direct gating block. Orthology transfer (ISO) from UniProtKB:P46934. Reason: The PAINT/ISO assertion is consistent with Nedd4-family suppression of ENaC, but the effect is a consequence of the E3 ligase activity (surface removal), and in vivo the paralog Nedd4-2 is the dominant ENaC regulator. Kept as non-core. Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) PMID:9351815 Our results suggest that ENaC function is regulated by ubiquitination file:rat/Nedd4/Nedd4-uniprot.txt regulates the activity of the epithelial Na(+) channel (ENaC) through ubiquitination, degradation and intracellular retention |
| GO:0019899 enzyme binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 binds many enzymes (E2 UBE2D2, kinases such as TNIK, NDFIP-activated complexes, USP13). Orthology transfer (ISO) from UniProtKB:P46934. Reason: True but uninformative about the specific partner; retained as non-core. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A |
| GO:0019904 protein domain specific binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: WW and C2 domain-mediated interactions with partner protein domains (e.g. GRB10 SH2 domain). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Accurate but peripheral binding description; the informative mechanism is captured by proline-rich region binding. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt WW domains are involved in recognizing PPxY motifs in substrate proteins |
| GO:0023051 regulation of signaling | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of signaling is entailed by negative regulation of VEGFR signaling pathway kept in this review. Electronic (IEA) mapping. Reason: ARBA term without added information. |
| GO:0030948 negative regulation of vascular endothelial growth factor receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 promotes VEGFR-2 degradation, reportedly independently of its ligase activity. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Ortholog-supported but mechanistically atypical; non-core. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity |
| GO:0030948 negative regulation of vascular endothelial growth factor receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nedd4 promotes VEGFR-2 degradation, reportedly independently of its ligase activity. Orthology transfer (ISS) from UniProtKB:P46935. Reason: Ortholog-supported but mechanistically atypical; non-core. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity |
| GO:0031175 neuron projection development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nedd4-1 promotes dendrite (neurite) growth by ubiquitinating Rap2A. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Correct, but the more precise regulation of dendrite morphogenesis is the specific supported process. Supporting Evidence: PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites |
| GO:0031175 neuron projection development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-1 promotes dendrite (neurite) growth by ubiquitinating Rap2A. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Correct, but the more precise regulation of dendrite morphogenesis is the specific supported process. Supporting Evidence: PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites |
| GO:0031623 receptor internalization | IBA GO_REF:0000033 | ACCEPT | Summary: Ubiquitination by Nedd4 triggers internalization of receptors (IGF1R, FGFR1, AMPA receptors). IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Central cell-biological outcome of Nedd4 activity on membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0031623 receptor internalization | ISO GO_REF:0000121 | ACCEPT | Summary: Ubiquitination by Nedd4 triggers internalization of receptors (IGF1R, FGFR1, AMPA receptors). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Central cell-biological outcome of Nedd4 activity on membrane substrates. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0031698 beta-2 adrenergic receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 interacts with ADRB2 and mediates its agonist-induced ubiquitination and lysosomal degradation. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Substrate binding for a specific receptor; peripheral to the core ligase function. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Interacts with ADRB2 |
| GO:0032801 receptor catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Nedd4 promotes lysosomal degradation of receptors (IGF1R, FGFR1, GluA1, ADRB2). IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Directly follows from ubiquitin-dependent receptor internalization and sorting. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes file:rat/Nedd4/Nedd4-uniprot.txt Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes |
| GO:0032801 receptor catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 promotes lysosomal degradation of receptors (IGF1R, FGFR1, GluA1, ADRB2). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Directly follows from ubiquitin-dependent receptor internalization and sorting. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes file:rat/Nedd4/Nedd4-uniprot.txt Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes |
| GO:0032991 protein-containing complex | ISO GO_REF:0000121 | TOO GENERAL | Summary: Protein-containing complex is entailed by ubiquitin ligase complex, retained in this review. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Uninformative parent of GO:0000151. Supporting Evidence: PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A |
| GO:0034644 cellular response to UV | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: UV-triggered recruitment of NEDD4 to stalled RNAPII and its ubiquitylation. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Ortholog-supported, peripheral. Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells |
| GO:0035255 ionotropic glutamate receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 associates with AMPA receptor subunits (GluA1) in neurons and ubiquitinates them. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Substrate binding supported by rat neuronal co-immunoprecipitation; non-core relative to the ligase activity. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. |
| GO:0042110 T cell activation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 promotes conversion of naive into activated T cells by degrading Cbl-b. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Mouse genetic evidence; non-core. Supporting Evidence: PMID:18931680 Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells |
| GO:0042176 regulation of protein catabolic process | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of protein catabolic process is entailed by positive regulation of protein catabolic process and the postsynaptic protein catabolism term kept here. Electronic (IEA) mapping. Reason: ARBA term without added information. |
| GO:0042391 regulation of membrane potential | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Effects on membrane potential are an indirect consequence of channel down-regulation. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Too indirect to be a process Nedd4 participates in. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION |
| GO:0042921 nuclear receptor-mediated glucocorticoid signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 (as RPF1) was reported to enhance steroid receptor transcriptional activity. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Older, peripheral finding transferred by orthology. |
| GO:0043130 ubiquitin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: HECT domains of the Nedd4 family carry a non-covalent ubiquitin-binding exosite used for processive chain formation. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Plausible structural feature of the HECT domain transferred from human; supports but is not itself the core function. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 ubiquitination of membrane proteins (GluA1, IGF1R, FGFR1) drives endocytic sorting to lysosomes. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Specific and well supported degradation route for its membrane substrates. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome file:rat/Nedd4/Nedd4-uniprot.txt Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes |
| GO:0044325 transmembrane transporter binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 binds ENaC subunits (a transmembrane transporter) through WW domain-PY motif interactions. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Correct substrate binding (ENaC), demonstrated for rat Nedd4; peripheral to the core catalytic function. Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) |
| GO:0045732 positive regulation of protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 promotes degradation of specific substrates (e.g. Cbl-b in T cells, GluA1). Orthology transfer (ISO) from MGI:MGI:97297. Reason: Reflects the downstream consequence of its ligase activity; non-core. Supporting Evidence: PMID:18931680 Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation |
| GO:0045732 positive regulation of protein catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4 promotes degradation of specific substrates (e.g. Cbl-b in T cells, GluA1). Orthology transfer (ISO) from UniProtKB:P46934. Reason: Reflects the downstream consequence of its ligase activity; non-core. Supporting Evidence: PMID:18931680 Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation |
| GO:0046824 positive regulation of nucleocytoplasmic transport | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human NEDD4; ubiquitination by NEDD4 has been linked to nucleocytoplasmic shuttling of substrates. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral, substrate-specific effect. |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-1 colocalizes with Rap2A and TNIK in the perinuclear region of neurons. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Supported by colocalization data; non-core. Supporting Evidence: PMID:20159449 Rap2A and TNIK are enriched and colocalized with Nedd4-1 in the perinuclear region of neurons |
| GO:0048514 blood vessel morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Nedd4-1 knockout embryos show vascular abnormalities. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Developmental phenotype; non-core. Supporting Evidence: PMID:20026598 disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities |
| GO:0048814 regulation of dendrite morphogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: Nedd4-1 forms a complex with TNIK and Rap2A and mono-ubiquitinates Rap2A, inhibiting Rap2/TNIK signalling and promoting dendrite growth and arborization; knockout neurons have shorter, less complex dendrites rescued by wild-type but not catalytically inactive Nedd4-1. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Best-characterized neuronal role, with direct mechanistic evidence for the ligase acting on a defined substrate. Supporting Evidence: PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites file:rat/Nedd4/Nedd4-uniprot.txt Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development |
| GO:0048814 regulation of dendrite morphogenesis | IDA PMID:20159449 Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls... | ACCEPT | Summary: Nedd4-1 forms a complex with TNIK and Rap2A and mono-ubiquitinates Rap2A, inhibiting Rap2/TNIK signalling and promoting dendrite growth and arborization; knockout neurons have shorter, less complex dendrites rescued by wild-type but not catalytically inactive Nedd4-1. Reason: Best-characterized neuronal role, with direct mechanistic evidence for the ligase acting on a defined substrate. Supporting Evidence: PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites file:rat/Nedd4/Nedd4-uniprot.txt Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development |
| GO:0048814 regulation of dendrite morphogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: Nedd4-1 forms a complex with TNIK and Rap2A and mono-ubiquitinates Rap2A, inhibiting Rap2/TNIK signalling and promoting dendrite growth and arborization; knockout neurons have shorter, less complex dendrites rescued by wild-type but not catalytically inactive Nedd4-1. Electronic (IEA) mapping. Reason: Best-characterized neuronal role, with direct mechanistic evidence for the ligase acting on a defined substrate. Supporting Evidence: PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites file:rat/Nedd4/Nedd4-uniprot.txt Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development |
| GO:0048814 regulation of dendrite morphogenesis | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4-1 forms a complex with TNIK and Rap2A and mono-ubiquitinates Rap2A, inhibiting Rap2/TNIK signalling and promoting dendrite growth and arborization; knockout neurons have shorter, less complex dendrites rescued by wild-type but not catalytically inactive Nedd4-1. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Best-characterized neuronal role, with direct mechanistic evidence for the ligase acting on a defined substrate. Supporting Evidence: PMID:20159449 Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A PMID:20159449 Nedd4-1 KO leads to the development of shorter and less complex dendrites file:rat/Nedd4/Nedd4-uniprot.txt Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development |
| GO:0050807 regulation of synapse organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Loss of Nedd4-1 reduces synapse number secondary to impaired dendrite development. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Indirect consequence of the dendrite phenotype; non-core. Supporting Evidence: PMID:20159449 Taken together, these results show that Nedd4-1 loss causes impaired dendrite development, which in turn leads to a reduction in the number of otherwise normal synapses |
| GO:0050807 regulation of synapse organization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Loss of Nedd4-1 reduces synapse number secondary to impaired dendrite development. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Indirect consequence of the dendrite phenotype; non-core. Supporting Evidence: PMID:20159449 Taken together, these results show that Nedd4-1 loss causes impaired dendrite development, which in turn leads to a reduction in the number of otherwise normal synapses |
| GO:0050815 phosphoserine residue binding | ISO GO_REF:0000121 | UNDECIDED | Summary: Mouse-derived ISO for phosphoserine residue binding; the underlying experiment could not be traced and Nedd4 WW domains are canonical PY-motif binders rather than phospho-Ser/Thr readers. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Source evidence not accessible in this review; neither confirmed nor refuted. Propagation Review Root cause: UNRESOLVED |
| GO:0050816 phosphothreonine residue binding | ISO GO_REF:0000121 | UNDECIDED | Summary: Mouse-derived ISO for phosphothreonine residue binding; underlying evidence not traced. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Source evidence not accessible in this review; neither confirmed nor refuted. Propagation Review Root cause: UNRESOLVED |
| GO:0050847 progesterone receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 (RPF1) reported to enhance progesterone receptor signalling. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Older, peripheral finding transferred by orthology. |
| GO:0051049 regulation of transport | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of transport is entailed by negative regulation of sodium ion transport kept in this review. Electronic (IEA) mapping. Reason: ARBA term without added information. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human NEDD4 (PTEN ubiquitination). Mouse knockout data argue PTEN is not a major in vivo Nedd4-1 target in neurons. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Disputed mechanism; peripheral. |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Nedd4 is a HECT-domain E3 ubiquitin ligase; ubiquitin protein ligase activity is its defining molecular function, supported by the conserved HECT domain, phylogenetic inference and rat-relevant ubiquitination assays. IBA from the PAINT ancestral node; rat Nedd4 sits in the NEDD4 clade with no sign of divergence. Reason: Core catalytic activity. Catalytically inactive (Cys-to-Ser) Nedd4-1 fails to ubiquitinate Rap2A, showing the HECT ligase activity itself is responsible. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Nedd4 is a HECT-domain E3 ubiquitin ligase; ubiquitin protein ligase activity is its defining molecular function, supported by the conserved HECT domain, phylogenetic inference and rat-relevant ubiquitination assays. Electronic (IEA) mapping. Reason: Core catalytic activity. Catalytically inactive (Cys-to-Ser) Nedd4-1 fails to ubiquitinate Rap2A, showing the HECT ligase activity itself is responsible. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0061630 ubiquitin protein ligase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is a HECT-domain E3 ubiquitin ligase; ubiquitin protein ligase activity is its defining molecular function, supported by the conserved HECT domain, phylogenetic inference and rat-relevant ubiquitination assays. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Core catalytic activity. Catalytically inactive (Cys-to-Ser) Nedd4-1 fails to ubiquitinate Rap2A, showing the HECT ligase activity itself is responsible. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0061630 ubiquitin protein ligase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is a HECT-domain E3 ubiquitin ligase; ubiquitin protein ligase activity is its defining molecular function, supported by the conserved HECT domain, phylogenetic inference and rat-relevant ubiquitination assays. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Core catalytic activity. Catalytically inactive (Cys-to-Ser) Nedd4-1 fails to ubiquitinate Rap2A, showing the HECT ligase activity itself is responsible. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0061630 ubiquitin protein ligase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Nedd4 is a HECT-domain E3 ubiquitin ligase; ubiquitin protein ligase activity is its defining molecular function, supported by the conserved HECT domain, phylogenetic inference and rat-relevant ubiquitination assays. Orthology transfer (ISS) from UniProtKB:P46934. Reason: Core catalytic activity. Catalytically inactive (Cys-to-Ser) Nedd4-1 fails to ubiquitinate Rap2A, showing the HECT ligase activity itself is responsible. Supporting Evidence: file:rat/Nedd4/Nedd4-uniprot.txt E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates PMID:20159449 The ubiquitination of Rap2A was abolished when catalytically inactive instead of WT Nedd4-1 was used file:rat/Nedd4/Nedd4-uniprot.txt Pfam; PF00632; HECT; 1. |
| GO:0070063 RNA polymerase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human NEDD4 associates with and ubiquitylates RNA polymerase II after UV damage. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Substrate binding; non-core. Supporting Evidence: PMID:17996703 we identified Nedd4 as an E3 that associates with and ubiquitylates RNAPII in response to UV-induced DNA damage in human cells file:rat/Nedd4/Nedd4-uniprot.txt Ubiquitinates POLR2A |
| GO:0070064 proline-rich region binding | ISO GO_REF:0000121 | ACCEPT | Summary: The WW domains of rat Nedd4 bind the proline-rich PY motifs (XPPXY) of ENaC subunits and other substrates; this is the substrate-recognition mechanism of the ligase. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Directly demonstrated for rat Nedd4 with rat ENaC (yeast two-hybrid, in vitro binding, NMR structure of WW3-betaENaC PY peptide). Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) file:rat/Nedd4/Nedd4-uniprot.txt WW domains are involved in recognizing PPxY motifs in substrate proteins |
| GO:0070064 proline-rich region binding | ISO GO_REF:0000121 | ACCEPT | Summary: The WW domains of rat Nedd4 bind the proline-rich PY motifs (XPPXY) of ENaC subunits and other substrates; this is the substrate-recognition mechanism of the ligase. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Directly demonstrated for rat Nedd4 with rat ENaC (yeast two-hybrid, in vitro binding, NMR structure of WW3-betaENaC PY peptide). Supporting Evidence: PMID:8665844 the rNedd4-WW domains mediate this association by binding to the P2 regions, which include the PY motifs (XPPXY) file:rat/Nedd4/Nedd4-uniprot.txt WW domains are involved in recognizing PPxY motifs in substrate proteins |
| GO:0070534 protein K63-linked ubiquitination | IDA PMID:20159449 Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls... | ACCEPT | Summary: Nedd4-family HECT E3s preferentially assemble K63-linked chains; Rap2A is partly K63-di-ubiquitinated by Nedd4-1. Reason: Curator IDA, consistent with the known K63 preference of Nedd4. Supporting Evidence: PMID:20159449 indicating that a minor fraction of Rap2A is modified by Nedd4-1 via K63-linked di-ubiquitination file:rat/Nedd4/Nedd4-uniprot.txt Specifically ubiquitinates 'Lys-63' in target proteins |
| GO:0098978 glutamatergic synapse | IDA PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: Nedd4 is enriched in synaptosomes and associates with AMPA receptors at glutamatergic synapses of rat neurons. Reason: Supported synaptic localization (SynGO, rat neurons); this is where Nedd4 acts on AMPA receptors, one of its best-characterized neuronal functions. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000117 | ACCEPT | Summary: Nedd4 is enriched in synaptosomes and associates with AMPA receptors at glutamatergic synapses of rat neurons. Electronic (IEA) mapping. Reason: Supported synaptic localization (SynGO, rat neurons); this is where Nedd4 acts on AMPA receptors, one of its best-characterized neuronal functions. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0098978 glutamatergic synapse | IEP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: Nedd4 is enriched in synaptosomes and associates with AMPA receptors at glutamatergic synapses of rat neurons. Reason: Supported synaptic localization (SynGO, rat neurons); this is where Nedd4 acts on AMPA receptors, one of its best-characterized neuronal functions. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0098978 glutamatergic synapse | IMP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: Nedd4 is enriched in synaptosomes and associates with AMPA receptors at glutamatergic synapses of rat neurons. Reason: Supported synaptic localization (SynGO, rat neurons); this is where Nedd4 acts on AMPA receptors, one of its best-characterized neuronal functions. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | ACCEPT | Summary: Nedd4 is enriched in synaptosomes and associates with AMPA receptors at glutamatergic synapses of rat neurons. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Supported synaptic localization (SynGO, rat neurons); this is where Nedd4 acts on AMPA receptors, one of its best-characterized neuronal functions. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization | IDA PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: In rat hippocampal neurons, Nedd4-1 ubiquitinates GluA1 and is required for AMPA-induced AMPA receptor endocytosis and lysosomal sorting; knockdown abolishes AMPAR ubiquitination. Reason: Direct mechanism (substrate ubiquitination) in rat neurons from two independent laboratories. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 knockdown of Nedd4 by specific siRNAs abolishes AMPAR ubiquitination |
| GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization | IEP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: In rat hippocampal neurons, Nedd4-1 ubiquitinates GluA1 and is required for AMPA-induced AMPA receptor endocytosis and lysosomal sorting; knockdown abolishes AMPAR ubiquitination. Reason: Direct mechanism (substrate ubiquitination) in rat neurons from two independent laboratories. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 knockdown of Nedd4 by specific siRNAs abolishes AMPAR ubiquitination |
| GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization | IMP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | ACCEPT | Summary: In rat hippocampal neurons, Nedd4-1 ubiquitinates GluA1 and is required for AMPA-induced AMPA receptor endocytosis and lysosomal sorting; knockdown abolishes AMPAR ubiquitination. Reason: Direct mechanism (substrate ubiquitination) in rat neurons from two independent laboratories. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 knockdown of Nedd4 by specific siRNAs abolishes AMPAR ubiquitination |
| GO:0099524 postsynaptic cytosol | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Postsynaptic cytosolic pool inferred from mouse; consistent with Nedd4 action on postsynaptic AMPA receptors. Orthology transfer (ISO) from MGI:MGI:97297. Reason: Peripheral, context-specific localization. Supporting Evidence: PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. |
| GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission | IDA PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1-dependent ubiquitination targets GluA1 for lysosomal degradation at synapses, altering excitatory transmission. Reason: Supported by rat neuron studies; a synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. |
| GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission | IEP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1-dependent ubiquitination targets GluA1 for lysosomal degradation at synapses, altering excitatory transmission. Reason: Supported by rat neuron studies; a synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. |
| GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission | IMP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1-dependent ubiquitination targets GluA1 for lysosomal degradation at synapses, altering excitatory transmission. Reason: Supported by rat neuron studies; a synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome PMID:21338354 Nedd4 is enriched in synapses, co-distributes and physically associates with AMPAR subunits. |
| GO:0140252 regulation protein catabolic process at postsynapse | IDA PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1 regulates degradation of postsynaptic AMPA receptors. Reason: Supported; synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0140252 regulation protein catabolic process at postsynapse | IEP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1 regulates degradation of postsynaptic AMPA receptors. Reason: Supported; synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:0140252 regulation protein catabolic process at postsynapse | IMP PMID:21148011 Activity-dependent ubiquitination of GluA1 mediates a distin... | KEEP AS NON CORE | Summary: Nedd4-1 regulates degradation of postsynaptic AMPA receptors. Reason: Supported; synaptic context of the core degradative function. Supporting Evidence: PMID:21148011 ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome |
| GO:1903765 negative regulation of potassium ion export across plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human NEDD4 negative regulation of potassium channel activity. Orthology transfer (ISO) from UniProtKB:P46934. Reason: Peripheral consequence of channel ubiquitination. |
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Download this section (compressed HTML)Q: Which of the many reported Nedd4-1 substrates (ENaC, IGF1R, FGFR1, GluA1, Rap2A, MTMR4) are physiologically ubiquitinated by Nedd4-1 rather than by its paralog Nedd4-2 in rat tissues?
Q: Is MTMR4 ubiquitinated and degraded by endogenous rat Nedd4 in denervated skeletal muscle, and does this contribute to atrophy?
Q: What is the experimental basis of the mouse phosphoserine/phosphothreonine residue binding annotations transferred to rat Nedd4 (GO:0050815, GO:0050816)?
Experiment: Muscle-specific Nedd4 knockdown or knockout in rat denervation atrophy, measuring endogenous MTMR4 ubiquitination, MTMR4 levels and fibre cross-sectional area.
Experiment: Quantitative ubiquitin-remnant proteomics in Nedd4-1 versus Nedd4-2 depleted rat neurons to define paralog-specific synaptic substrates.
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